title: The effects of oral treatment with transfluthrin on the urothelium of rats and its metabolite, tetrafluorobenzoic acid on urothelial cells in vitro.
abstract: Transfluthrin, a pyrethroid insecticide, induced urinary bladder tumors in rats but not in mice in 2-year bioassays. We investigated the urothelial effects of transfluthrin in vivo in rats and the effects of its major metabolite tetrafluorobenzoic acid (TFBA) in vitro on rat (MYP3) and human (1T1) urothelial cell lines. Rats were fed diet containing 0, 2000 or 5000 (with and without 1.25% NH(4)Cl) ppm transfluthrin for 4 weeks or 0 or 2000 ppm transfluthrin for 13 weeks. After 4 weeks, there was no evidence of hyperplasia or increased proliferation in any treatment group. After 13 weeks treatment with 2000 ppm, cytotoxicity and necrosis of the rat urothelial superficial layer were detected by scanning electron microscopy. The urinary concentration of TFBA in rats fed 2000 ppm transfluthrin was 2.94±0.67 mM. The LC(50) of TFBA was 2.25 mM for MYP3 cells and 2.43 mM for 1T1 cells. These studies support cytotoxicity and regenerative proliferation as the mechanism for induction of bladder tumors with high oral doses of transfluthrin due to metabolism of transfluthrin to the weakly cytotoxic TFBA which is excreted at high concentrations in the urine of rats administered high doses of transfluthrin (≥2000 ppm) for an extended period.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA.
authors.forename: Masanao
authors.initials: M
authors.lastname: Yokohira
authors.forename: Lora L
authors.initials: LL
authors.lastname: Arnold
authors.forename: Sophie
authors.initials: S
authors.lastname: Lautraite
authors.forename: Larry
authors.initials: L
authors.lastname: Sheets
authors.forename: Sheila
authors.initials: S
authors.lastname: Wason
authors.forename: Bernhard
authors.initials: B
authors.lastname: Stahl
authors.forename: David
authors.initials: D
authors.lastname: Eigenberg
authors.forename: Karen L
authors.initials: KL
authors.lastname: Pennington
authors.forename: Satoko
authors.initials: S
authors.lastname: Kakiuchi-Kiyota
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000818:Animals; D001565:Benzoates / Q000633:toxicity*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003521:Cyclopropanes / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005464:Fluorobenzenes / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011722:Pyrethrins / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology; D019459:Urothelium / Q000187:drug effects* / Q000648:ultrastructure
chemical_list: C560614:2,3,5,6-tetrafluorobenzoic acid; D001565:Benzoates; D003521:Cyclopropanes; D005464:Fluorobenzenes; D007306:Insecticides; D011722:Pyrethrins; C560613:transfluthrin